Abstract |
Regulators of G protein signaling (RGS) proteins, modulate G protein coupled receptor
responsiveness through their GTPase activity. RGS exert signaling termination by binding to
activated Gα subunit of G proteins via their RGS domain. We are particularly interested in
RGS9-2 a multifunctional protein and a member of RGS family which is highly concentrated
in striatum but also localized in regions that mediate addiction and analgesia. We have
previously shown that RGS9-/- (KO) mice show enhanced morphine analgesia and delayed
development of tolerance (Zachariou et al.,2003). In our effort to comprehend the mechanism
via which RGS9-2 modulates opioid actions we investigated the role of RGS9-2 in mu opioid
receptor functional responses. According to our data, in PC12 and MEF cells RGS9-2 delays
morphine or DAMGO-mediated MOR endocytosis. To exert this action, RGS9-2 is located to
the cell membrane through the binding of its DEP domain to transmembrane proteins. The
overexpression of RGS9-2 in PC12 cells leads to inhibition of ERK phosphorylation in an
agonist dependent manner, a system that is affected by MOR activation. In striatum the levels
of RGS9 are exclusively regulated by morphine and its expression leads to inhibition of ERK
stimulation which is enhanced when RGS9 is not expressed (RGS9-2-/- tissues). The
participation of RGS9 in the signaling complexes that are formed after acute or chronic
stimulation of MOR by opioids, gives an additive role to RGS9. Depending on the agonist
stimulation and protein interactions with Gβ5 and Gα subunits, as well as β-arrestin2, RGS9
can act as a positive or as a negative regulator of the analgesic effect.
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